Nuclear extracts from differentiating keratinocytes contain Fra-1, Fra- 2, Jun B, Jun D, and c-Jun proteins that bind to the AP-1 DNA binding sequence present in a variety of genes involved in keratinocyte differentiation. CREB family proteins, CREB and CREM a, also are detected in AP- 1 complexes from differentiating keratinocytes. Dominant-negative CREB mutants enhance AP-1 reporter activity when transfected into keratinocytes whereas transfection of CREM a suppresses AP-1 activity. These results indicate that the CREB family serves as a modulator of AP-1 activity during keratinocyte differentiation. The expression of the nuclear body protein PML also increases in differentiating keratinocytes. Overexpression of PML by transfection into basal keratinocytes causes growth arrest and apoptosis. Apoptosis is independent of p53 and pRb expression. These data suggest PML contributes to the growth suppression and cell death associated with keratinocyte differentiation. Transgenic mice have been generated that target overexpression of PKC a to epidermal basal cells and the outer root sheath of hair follicles. When transgenic skin is exposed to phorbol esters by topical application, there is a marked inflammatory infiltrate into the epidermis, and the hair follicles degenerate. In vitro, transgenic keratinocytes are sensitive to phorbol ester toxicity. cDNA array comparison of mRNA patterns from wildtype and transgenic keratinocytes after phorbol ester treatment indicate that the cytokines MIP-2. G-CSF, MIP-1 and CCR-1 are upregulated in the transgenic cells. These factors may be candidates responsible for the inflammatory infiltrate into the epidermis in vivo. Studies on a stromal cell line that enhances tumor growth and causes skin wrinkling suggest that IGF-2 secretion could be involved. - Differentiation, hair follicle, keratinocyte, Phosphorylation, protein kinase C, transcriptional regulation, - Human Tissues, Fluids, Cells, etc.